The assembly of proteins into insoluble aggregates is a hallmark of several diseases, including many neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and prion diseases. Protein aggregation, however, is by no means restricted to the central nervous system (CNS) and also occurs in diseases as diverse as Type II diabetes and Inclusion body myositis/myopathy.
Each of the relevant neurodegenerative diseases involves selective neuronal vulnerability with degeneration in specific brain regions and deposits of abnormal proteins in neurons, other cells or extracellularly. It is increasingly recognised that these neurodegenerative diseases have common cellular and molecular mechanisms including protein aggregation and inclusion body formation. The aggregates usually consist of fibres containing misfolded proteins which may have a β-sheet conformation, and there is partial but not perfect overlap among the cells in which abnormal proteins are deposit and the cells that degenerate.
Although each disease is primarily associated with the aggregation of a specific protein, there is a considerable overlap and the same protein may be found to aggregate across a variety of diseases. For example, AD is primarily associated with aggregated amyloid-β and tau proteins, PD with aggregates comprising protein α-synuclein bound to ubiquitin and HD with mutant Huntingtin. It has been reported, however, that although α-synuclein aggregates are invariant characteristics of PD, they also occur in AD. Similarly, TDP-43 aggregation is associated with ALS and frontotemporal dementia but also with many (30-50%) cases of AD.
Despite the well-reported association between protein aggregates and neurodegenerative diseases, the causative mechanisms leading to the generation of aggregates remain elusive. A consequence of the poor understanding of the processes involved in the generation of protein aggregates and the subsequent neurodegenerative disorders with which they are associated is an absence of curative therapeutic strategies. There is currently no curative treatment for any neurodegenerative disease associated with protein aggregation. As such, current treatment strategies focus on palliative care and aim to repress the appearance of symptoms for as long as possible.
In most neurodegenerative disorders the occurrence of familial mutations are extremely rare and the majority of cases occur without any family history. Current methods to study protein aggregation rely largely on the use of recombinant proteins in vitro or the forced expression of proteins, frequently harbouring familial disease-causing mutations, in cells or model organisms. While these methods may suffice for the study of single proteins they rarely replicate the aggregation of all proteins associated with the particular disease. For example, transgenic animal models of AD (transgene expression of mutated APP and/or PSEN1 or PSEN2) do show amyloid-β aggregation but do not demonstrate tau aggregation and thus lack one of the hallmarks of human AD. Currently, to replicate tau aggregation, mutations that have never been found in human AD must be introduced into the MAPT gene. The failure rate of drugs targeting neurodegenerative diseases is high, despite the fact that some drugs, for example for AD, demonstrate efficacy in animal models of disease. Thus it is likely that current models do not faithfully represent the human disease to which they are directed.
There is thus a need for an improved model of protein aggregation that is not associated with these disadvantages.